(Hypertension. 1996;27:607-612.)
© 1996 American Heart Association, Inc.
Articles |
Bradykinin and Protein Kinase C Activation Fail to Stimulate Renal Sensory Neurons in Hypertensive Rats
From the Department of Internal Medicine, University of Iowa College of Medicine and Department of Veterans Affairs Medical Center, Iowa City.
Correspondence to Ulla C. Kopp, PhD, Department of Internal Medicine, University of Iowa College of Medicine, Iowa City, IA 52242.
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Abstract |
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Abstract In normotensive rats, renal sensory receptor activation by increased ureteral pressure results in increased ipsilateral afferent renal nerve activity, decreased contralateral efferent renal nerve activity, and contralateral diuresis and natriuresis, a contralateral inhibitory renorenal reflex response. In spontaneously hypertensive rats (SHR), increasing ureteral pressure fails to increase afferent renal nerve activity. The nature of the inhibitory renorenal reflexes indicates that an impairment of the renorenal reflexes would contribute to the increased efferent renal nerve activity in SHR. We therefore examined whether there was a general decrease in the responsiveness of renal sensory receptors in SHR by comparing the afferent renal nerve activity responses to bradykinin in SHR and Wistar-Kyoto rats (WKY). In WKY, renal pelvic perfusion with bradykinin at 4, 19, 95, and 475 µmol/L increased afferent renal nerve activity by 1066±704, 2127±1121, 3517±1225, and 4476±1631%·second (area under the curve of afferent renal nerve activity versus time). In SHR, bradykinin at 4 to 95 µmol/L failed to increase afferent renal nerve activity. Bradykinin at 475 µmol/L increased afferent renal nerve activity in only 6 of 10 SHR. In WKY, renal pelvic perfusion with the phorbol ester 4ß-phorbol 12,13-dibutyrate, known to activate protein kinase C, resulted in a peak afferent renal nerve activity response of 24±4%. However, 4ß-phorbol 12,13-dibutyrate failed to increase afferent renal nerve activity in SHR. These findings demonstrate decreased responsiveness of renal pelvic sensory receptors to bradykinin in SHR. The impaired afferent renal nerve activity responses to bradykinin in SHR may be due to a lack of protein kinase C activation or a defect in the intracellular signaling mechanisms distal to protein kinase C activation.
Key Words: protein kinases • rats, inbred SHR • renal nerve • phorbols
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Introduction |
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In normotensive rats, activation of renal pelvic mechanoreceptors by increased ureteral pressure results in an increase in ipsilateral ARNA, a decrease in contralateral efferent renal nerve activity, and a contralateral diuresis and natriuresis, a contralateral inhibitory renorenal reflex response.1
Accumulating evidence indicates that the renal nerves contribute to the pathogenesis of hypertension in SHR.2 Peripheral sympathetic nerve activity and, in particular, renal sympathetic nerve activity are enhanced in SHR. Numerous studies have shown that the arterial and cardiopulmonary baroreflexes are impaired in SHR (eg, see References 3 and 4). Likewise, our previous studies showed that the renorenal reflex responses to renal mechanoreceptor stimulation are impaired in SHR.5 The inhibitory nature of the renorenal reflexes suggests that an impairment of these reflexes would contribute to the increased renal sympathetic nerve activity observed in SHR.
Our previous studies have suggested an important role for renal prostaglandins in renal pelvic mechanoreceptor activation in normotensive rats.6 7 Increasing ureteral pressure results in a release of PGE from the renal pelvic wall.8 Furthermore, the renorenal reflex responses to renal mechanoreceptor stimulation were suppressed by renal pelvic perfusion with indomethacin or an essential fatty acid–deficient diet and restored by addition of PGE2 to the renal pelvic perfusate.6 7
Bradykinin, a known activator of sensory neurons in various organs,9 increases renal prostaglandin synthesis.10 Renal pelvic perfusion with bradykinin results in increases in ipsilateral ARNA and contralateral urinary sodium excretion that depend on intact prostaglandin synthesis in Sprague-Dawley rats,11 a response similar to that produced by increased ureteral pressure.6 7 Taken together, our previous findings suggest an important role for renal pelvic prostaglandins in renal sensory receptor activation by both increased ureteral pressure and bradykinin. The importance of prostaglandins in renal sensory receptor activation is of interest in view of previous studies showing that the decreased baroreceptor activity in renovascular hypertensive rabbits was related to impaired prostaglandin synthesis.12 Whether renal prostaglandin synthesis is impaired in hypertensive subjects is controversial. Whereas some studies demonstrated decreased urinary PGE2 excretion in essential hypertensive patients,13 14 15 other studies reported no differences in urinary PGE2 excretion between normotensive and hypertensive individuals.16 17 Similar conflicting findings have been observed in SHR. Urinary PGE2 excretion has been shown to be either increased18 or decreased.19 We performed the present study to examine whether decreased responsiveness of renal sensory receptors was specific to increased ureteral pressure or was observed also in response to other prostaglandin-dependent activators of renal sensory receptors in SHR, such as bradykinin.
Since the results of the present study showed that bradykinin resulted in suppressed activation of renal pelvic sensory receptors in SHR compared with their normotensive WKY controls, we performed further studies to examine whether the decreased ARNA responses to bradykinin in SHR were related to a defect in the intracellular signaling mechanisms elicited by bradykinin.
There is considerable evidence for bradykinin activating the phosphoinositide system through activation of receptors coupled to PLC via a Gq protein, which is distinct from Gs and Gi proteins.20 21 Activation of PLC generates two second messengers: diacylglycerol and inositol 1,4,5-trisphosphate. Inositol 1,4,5,-trisphosphate mobilizes calcium from the endoplasmic reticulum, and diacylglycerol activates PKC. The activated PKC acts synergistically with calcium to activate PLA2, which is the primary enzyme regulating arachidonic acid release from membrane phospholipids. We have recently shown that activation of PKC contributes importantly to activation of renal pelvic sensory receptors in normotensive rats.22 Activation of PKC by renal pelvic perfusion with the phorbol ester PDBu increased ARNA in rats on a normal diet but not in rats fed an essential fatty acid–deficient diet to produce depletion of endogenous arachidonic acid, suggesting a role for arachidonic acid metabolites in renal sensory activation by PDBu. Further studies showed that inhibition of PKC blocked the ARNA response to bradykinin, suggesting that activation of PKC contributes to bradykinin-mediated activation of renal sensory receptors. To examine whether the decreased responsiveness of the renal sensory receptors to bradykinin in SHR was related to a defect in bradykinin receptor–initiated events, we examined whether PDBu activated the renal pelvic sensory receptors to the same extent in SHR and WKY.
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Methods |
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The study was performed in male 11- to 14-week-old SHR weighing 260 to 350 g (mean weight, 290±5 g) and 9- to 14-week-old WKY weighing 320 to 500 g (mean weight, 380±10 g) (Taconic Farms, Germantown, NY). The experimental protocols were approved by the Institutional Animal Care and Use Committee of the University of Iowa and performed according to the Guide for the Care and Use of Laboratory Animals from the National Institutes of Health. Anesthesia was induced with 0.2 mmol/kg pentobarbital sodium IP (Abbott Laboratories) and maintained with an infusion of 0.04 mmol/kg per hour IV in isotonic saline at 50 µL/min.
Catheters were inserted into the femoral artery for measurement of arterial pressure (Statham transducer P23Db, Gould Instruments) and into the femoral vein for pentobarbital sodium infusion. Heart rate was recorded by a linear cardiotachometer (model P511, Grass Instrument Co) triggered by the arterial pressure.
All recordings were made on a Grass 7D polygraph connected to an IBM PS/2 model 30 computer via an A/D board (model DT 2801, Data Translation, Inc) for on-line data acquisition.
A left flank incision was performed and a polyethylene catheter (PE-10) inserted into the right ureter for urine collection. For perfusion of the left renal pelvis, a PE-10 catheter was inserted into a PE-60 catheter placed in the left ureter and advanced into the renal pelvis with its tip ending 1 to 2 mm beyond the tip of the PE-60 catheter.1 5 6 7 11 22 The renal pelvis was perfused at 20 µL/min throughout the experiment.
Renal Mechanoreceptor Stimulation
Ureteral pressure was
increased by raising the PE-60 catheter
inserted into the left ureter above the level of the
kidney.1 5 6 7 The PE-60
catheter was filled with 0.15 mol/L
NaCl. Ureteral pressure was recorded with a Statham P23Db
transducer connected to the ureteral catheter by a T tube
connector.
Recording of Renal Nerve Activity
One renal nerve branch was
isolated at the angle between the
aorta and left renal artery and placed on a bipolar silver wire
electrode (Cooner Wire) for recordings of multifiber renal
nerve activity. The electrode was fixed to the renal nerve with
silicone cement (Wacker Sil-Gel 604, Wacker-Chemie). The signals were
led by a high-impedance probe (Grass HIP511) to a band pass
amplifier (Grass P511) with a high-frequency cutoff at 3000 Hz and
a low-frequency cutoff at 30 Hz; they were amplified 20 000 times.
The output of the band-pass amplifier was fed to an oscilloscope
(Tektronix 5113) and to a resetting voltage integrator (Grass 7P10).
Renal nerve activity was integrated over 1-second intervals, the unit
of measure being microvolts per second per 1 second. Assessment of
renal nerve activity was done by its pulse-synchronous rhythmicity.
After identification and verification of renal nerve activity, the
renal nerve was sectioned and the distal part placed on the electrode
for ARNA recording. Postmortem renal nerve activity, assessed
by crushing the decentralized renal nerve bundle peripheral
to the recording electrode, was subtracted from all renal nerve
activity values. ARNA was expressed as a percentage of its baseline
value during the control
period.1 5 6 7 11 22
Experimental Protocols
Approximately 1.5 hours elapsed after
the end of surgery and the
start of the experiment to allow the rat to stabilize, as evidenced by
30 minutes of steady state urine collections and renal nerve
recordings. The rats were divided into two study groups.
Group 1:
Bradykinin
In 10 SHR and 7 WKY, bradykinin was administered into the
renal
pelvis at 4, 19, 95, and 475 µmol/L during four experimental periods
separated by 35-minute intervals. Each 5-minute experimental period was
bracketed by a 5-minute control and recovery period. Renal pelvis was
perfused with 0.15 mol/L NaCl (vehicle) when bradykinin was not
administered. Before bradykinin administration, ureteral pressure was
increased for 5 minutes for examination of the ARNA responses to renal
mechanoreceptor stimulation in SHR and WKY.
Group 2: PKC
Activation
In 10 SHR and 9 WKY, the renal pelvis was perfused with
0.1%
DMSO (vehicle) during a 10-minute control period. Then, the renal
pelvic perfusate was switched to PDBu at 1 µmol/L for 10
minutes. The renal pelvic perfusate was switched back from PDBu
to 0.1% DMSO for a 50-minute recovery period. In another 5 SHR and 5
WKY, the inactive phorbol ester PDD (1 µmol/L) was administered
instead of PDBu.
At the end of each experiment in groups 1 and 2, 8 µmol/L capsaicin was administered into the renal pelvis at a volume of 50 µL for examination of whether the decreased responsiveness of the renal sensory receptors to increased ureteral pressure, bradykinin, and PDBu in SHR was related to some nonspecific generalized unresponsiveness of the afferent renal nerves (eg, dissection damage).
Drugs
Bradykinin, PDBu, and PDD were from Sigma Chemical Co.
Bradykinin was dissolved in 0.15 mol/L NaCl. PDBu and PDD were
dissolved in DMSO and further diluted with 0.15 mol/L NaCl to a final
DMSO concentration of 1%.
Statistical Analyses
Systemic hemodynamics were measured and
averaged
over each period. In the PDBu and PDD experiments, ARNA was averaged
over each 5-minute period after the start of the PDBu or PDD renal
pelvic perfusion and calculated as percentage of the 10-minute control
period preceding administration of PDBu or PDD. In normotensive rats,
the ARNA responses to bradykinin increased in duration with increasing
concentrations. Therefore, the ARNA responses to bradykinin were
calculated as the area under the curve of time versus ARNA, where ARNA
was expressed as a percentage of its baseline value during the control
period immediately preceding each bradykinin dose. Friedman two-way
ANOVA was used to test whether ARNA was increased above baseline
control during bradykinin administration at various concentrations and
PDBu at various time points.23 Shortcut ANOVA was used for
multiple comparisons among groups.24 The Wilcoxon
matched-pairs signed rank test and Mann-Whitney U test
were applied to test the significance between two related and two
unrelated samples, respectively.23 Fisher's exact
probability test was used to examine whether the ARNA responses to
bradykinin at various concentrations differed between WKY and
SHR.23 A significance level of 5% was chosen. Data in
text and figures are expressed as mean±SE.
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Results |
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TopAbstractIntroductionMethods Results Discussion References |
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Group 1: Bradykinin
Figs 1
and
2 show results for
group 1. In WKY, increasing ureteral pressure by 16.4±0.6 mm Hg
increased ARNA 29±2% (P<.02). Renal pelvic perfusion with
bradykinin increased ARNA in a concentration-dependent fashion (Fig
1). The duration of the response to bradykinin at 4, 19, 95,
and 475
µmol/L was 50±24, 88±33, 136±40, and 157±46
seconds,
respectively. Basal mean arterial pressure (109±5
mm Hg) did not change significantly during the experiment. Mean
arterial pressure was not affected by renal pelvic
perfusion with bradykinin at 4 and 19 µmol/L but was transiently
decreased 8±4 and 12±5 mm Hg (P<.05) by bradykinin
at 95
and 475 µmol/L, respectively. Heart rate (356±16 bpm) was unaltered
by bradykinin.
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In SHR, increasing ureteral pressure by 16.8±0.4
mm Hg failed to
increase ARNA (2±1%). Renal pelvic perfusion with bradykinin at 4,
19, and 95 µmol/L increased ARNA above 0% in only 2, 4, and 3 of 10
SHR, respectively (Fig 2
), significantly less than in WKY, in
which
bradykinin at 4, 19, and 95 µmol/L increased ARNA in 6, 7, and 7 of 7
WKY, respectively. Bradykinin at 475 µmol/L increased ARNA above 0%
in 6 of 10 SHR. The average increase in 10 SHR produced by renal pelvic
perfusion with bradykinin at 4, 19, 95, and 475 µmol/L was 259±221,
671±491, 1209±1056, and 2151±815%·second,
respectively. Basal
mean arterial pressure (150±2 mm Hg) did not change
during the experiment. Mean arterial pressure was not
affected by renal pelvic perfusion with bradykinin at 4, 19, and 95
µmol/L but was transiently decreased 10±3 mm Hg by 475 µmol/L
bradykinin. Heart rate (362±12 bpm) was unaltered by bradykinin.
Renal pelvic administration of capsaicin increased ARNA 76±14% in SHR and 149±41% in WKY. These ARNA responses were not significantly different.
Group 2: PKC Activation
Fig 3 and the
Table show results for
group 2. In WKY, renal pelvic perfusion with PDBu resulted in a gradual
increase in ARNA that peaked 5 minutes after the PDBu perfusion was
stopped and remained significantly increased for 35 minutes (Fig
3).
Mean arterial pressure (99±4 mm Hg) and heart rate
(323±17 bpm) remained unchanged throughout the experiment. In SHR,
renal pelvic perfusion with PDBu failed to increase ARNA (Fig
3). Mean
arterial pressure (155±5 mm Hg) and heart rate (355±11
bpm) remained unchanged throughout the experiment.
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Renal pelvic administration of capsaicin resulted in similar increases in ARNA in SHR (77±12%) and WKY (103±12%).
The inactive
phorbol ester PDD did not alter ARNA in either WKY or SHR
(Table). Mean arterial pressure and heart rate were
125±4
mm Hg and 362±10 bpm in WKY and 165±11 mm Hg and 362±9
bpm in SHR.
Neither mean arterial pressure nor heart rate was affected
by PDD.
The ARNA responses to capsaicin were similar in SHR (111±17%) and WKY (133±57%).
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Discussion |
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TopAbstractIntroductionMethods Results Discussion References |
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The results of the present study show that renal pelvic perfusion with bradykinin failed to increase ARNA in the majority of SHR at concentrations that produced marked increases in ARNA in WKY. Further studies showed that renal pelvic perfusion with the phorbol ester PDBu increased ARNA in WKY but not in SHR. Taken together, these studies show a decreased responsiveness of renal pelvic sensory receptors to bradykinin and PDBu in SHR. The data suggest that the impaired responses of renal sensory receptors to bradykinin in SHR are due to impaired activation of PKC or a defect in the intracellular signaling mechanisms distal to PKC activation.
In WKY, renal pelvic perfusion with bradykinin at increasing concentrations resulted in graded increases in ARNA, ie, a response similar to that previously demonstrated in normotensive Sprague-Dawley rats.11 However, the responsiveness of renal sensory receptors to bradykinin was decreased in SHR. Nine of 10 SHR exhibited ARNA responses to bradykinin that were either absent or in the lower range of those observed in WKY; only 1 of 10 SHR showed an ARNA response that was above the average ARNA response seen in WKY. Furthermore, bradykinin at a supramaximal concentration for activation of renal sensory receptors in normotensive rats, 475 µmol/L (see Reference 11 and the present study), increased ARNA in only 6 of 10 rats. In agreement with our previous studies,5 increasing ureteral pressure failed to increase ARNA in SHR. Taken together, these studies show that renal pelvic sensory receptors in SHR display decreased responsiveness to various stimuli, including increased ureteral pressure and renal pelvic perfusion with hypertonic NaCl5 and bradykinin. Our studies in normotensive Sprague-Dawley rats have shown that activation of renal pelvic sensory receptors by these stimuli depends on intact renal prostaglandin synthesis.6 7 11 Impaired prostaglandin synthesis plays an important role in the decreased carotid baroreceptor activity demonstrated in renovascular hypertensive rabbits.12 Whether the impaired responsiveness of renal sensory receptors in SHR is related to impaired renal prostaglandin synthesis is not known. Previous studies show evidence for both increased and decreased renal prostaglandin synthesis. Both decreased and unaltered urinary PGE2 excretion have been reported in essential hypertensive patients.13 14 15 16 17 In SHR, there are reports of either increased or decreased urinary PGE2 excretion.18 19 However, both basal and stimulated PGE2 accumulation was shown to be less in most nephron segments in stroke-prone SHR compared with WKY.18
It is well known from studies in both neural and nonneural in vitro
preparations that bradykinin increases the release of PGE2
via activation of PLC.20 21 Whether the intracellular
signaling mechanisms elicited by the stimulation of various receptors
in the kidney are altered in SHR has been studied extensively.
Desensitization of renal 
1-adrenoceptor coupling to PLC
has been reported repeatedly in
SHR25 26 27 and has been
attributed to an age-related decrease in
Gq.26 This decrease appears to be specific to
the kidney, as it was not observed in cardiac or vascular smooth
muscle,28 29 indicating tissue-specific regulation of
G protein expression. Impaired regulation of proximal tubular
Na+,K+-ATPase activity by dopamine has
been ascribed to a defect in G protein regulation30 and
impaired dopamine-1 receptor coupling to PLC.31 Whether
PLC activity is increased or decreased in SHR appears to be related to
the stimuli and renal cell preparation used. Compared with WKY, in SHR
activation of PLC is impaired by dopamine in renal cortical
slices,32 enhanced by angiotensin, and
unchanged by vasopressin and endothelin in glomerular
mesangial cells.33 Furthermore, a defect in
dopamine-1 receptor adenylate cyclase coupling has been
implicated in the impaired inhibition of the proximal tubular
Na+-H+ exchange produced by dopamine in
SHR.34 35 However, this defect was not observed in
the
distal nephron.36 Furthermore, the reduced ability of the
dopamine-1 agonist fenoldopam and PGE2 to blunt the renal
vasoconstrictor responses to angiotensin in SHR was
suggested to be related to a defect in the coupling between adenylyl
cyclase and the dopamine and PGE2 receptors,
respectively.37 38
To examine whether the impaired ARNA responses to bradykinin in SHR were related to a defect in the intracellular signaling mechanisms proximal to PKC, we compared the ARNA responses to renal pelvic perfusion to PDBu in SHR and WKY in the present study. Tumor-promoting phorbol esters such as PDBu have a molecular structure similar to that of diacylglycerol. They mimic the effect of diacylglycerol by binding to the regulatory domain of PKC.20 39 In its resting state, PKC is present mainly in the cytosol. However, when the cell is stimulated, diacylglycerol concentration transiently rises in the plasma membrane and PKC is translocated to the membrane. The present results show that in WKY, renal pelvic perfusion with PDBu resulted in a gradual increase in ARNA that peaked 5 minutes after the renal pelvic perfusion with PDBu was stopped and remained significantly increased for 35 minutes, ie, a response similar to that we have previously shown in Sprague-Dawley rats.22 That the duration of the ARNA response was much longer than that produced by bradykinin was most likely because of the fact that phorbol esters, unlike diacylglycerol, are metabolically stable.39 The magnitude of the ARNA response to 1 µmol/L PDBu was less than that produced by bradykinin at 19 µmol/L and higher. The differences between the ARNA responses to bradykinin and PDBu may be related to the fact that bradykinin increases arachidonic acid release not only by activation of PKC but also by direct activation of PLA2.9 Our previous studies showed that the ARNA response to bradykinin was reduced but not abolished by PKC inhibition.22 Furthermore, only one concentration of PDBu was used in the present study. Although PDBu at this concentration (1 µmol/L) is known to activate PKC in vitro,40 41 it is not known whether PKC was maximally activated in vivo by PDBu at this concentration.
In contrast to the increase in ARNA produced by PDBu in WKY, renal pelvic perfusion with PDBu failed to increase ARNA in SHR. ARNA was unaltered by the inactive phorbol ester PDD in both SHR and WKY. Our previous studies have shown that renal pelvic perfusion with PDBu failed to increase ARNA in rats fed an essential fatty acid–deficient diet to produce depletion of arachidonic acid,22 suggesting a role for renal arachidonic acid metabolites in the activation of renal sensory receptors by PDBu. Our findings that renal pelvic perfusion with PDBu failed to increase ARNA in SHR are in apparent conflict with previous in vitro studies showing that phorbol esters produced similar inhibition of Na+,K+-ATPase in renal proximal tubular cells and similar increases in HCO3- absorption in medullary thick ascending limbs in SHR and WKY.31 42 However, as discussed above, possible defects in the intracellular mechanisms in SHR appear to be cell and organ specific. Taken together, our studies suggest that the lack of an increase in ARNA by PDBu in SHR is related to a defect in PKC activation per se or an impairment in the intracellular signaling mechanisms distal to PKC. If the impaired ARNA responses to bradykinin are related to a defect distal to PKC activation, the suppressed activation of renal sensory receptors may be related to reduced renal prostaglandin synthesis or impaired prostaglandin-mediated depolarization of renal sensory neurons.
The lack of an increase in ARNA in response to renal pelvic perfusion with bradykinin or PDBu in SHR was not due to a nonspecific unresponsiveness of the renal nerves, because renal pelvic administration of capsaicin, known to depolarize sensory neurons by increasing cation conductance,43 increased ARNA 84±8% (n=24) in SHR, a response not significantly different from that in WKY (126±19%, n=21), as tested at the end of each experiment.
In summary, the results of the present study show that renal pelvic perfusion with bradykinin and the phorbol ester PDBu increased ARNA in WKY but not SHR. These results suggest that the decreased responsiveness of renal pelvic sensory receptors to bradykinin in SHR is due to lack of activation of PKC or related to a defect in the intracellular signaling mechanisms distal to PKC activation.
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Acknowledgments |
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This work was supported by grants from the Department of Veterans Affairs and the National Heart, Lung, and Blood Institute, Specialized Center of Research, Grant HL-44546, and the American Heart Association, Iowa Affiliate, Grant-in-Aid IA-95-GS-43.
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